The goal of the proposed research is to understand the molecular mechanisms underlying the abuse of phencyclidine (PCP) and related drugs such as ketamine. These drugs possess anesthetic, analgesic, and stimulant psychotomimetic properties. A specific (3H) PCP binding assay developed by us provides a means by which the interactions of these drugs with the brain will be studied directly. Further characterization of the PCP binding site will emphasize a detailed understanding of its biochemical properties. Differences in clinical effects among PCP-like drugs will be elucidated by comparisons of their binding characteristics. Biochemical correlates of abuse, tolerance and withdrawal will be examined by binding studies performed with brain tissue from animals tolerant to, withdrawing from or chronically self-administering PCP. Interactions of PCP binding sites with other CNS receptors and known neurochemical pathways will be studied. The binding assay will be used to elucidate structure-function relationships of PCP-like drugs in order to design or search for a PCP antagonist, as well as anesthetic derivatives devoid of abuse potential. A search for an endogenous ligand of the PCP binding site will be carried out by assaying the abilities of brain fractions to inhibit 3H PCP binding. Together, these studies are hoped to yield a pharmacological approach for intervention in one of the nation's most pressing drug abuse problems.